Gyrate atrophy of the choroid and retina (GA) is a rare inherited form of chorioretinal degeneration characterized by 10 x 15 x fold increases in the concentration of ornithine in all body fluids and deficiency of the mitochondrial matrix enzyme ornithine-Delta-aminotransferase (OAT). The goals of the proposed research include: (1) delineation of heterogeneity in the mutations leading to GA and relating this to clinical variability; (ii) elucidating the pathophysiologic mechanisms involved in the chorioretinal degeneration and cataract formation; (iii) evaluating the therapeutic efficacy of an arginine-restricted diet and several dietary adjuncts; and (iv) Screening the offspring of chemically mutagenized mice for a genetic model of GA. The methodologies used to approach these goals will include: detailed ophthalmologic examination; analysis of amino acids and their metabolites and guanidino compounds in patient and animal samples; somatic cell genetic techniques including assay of OAT activity, antigen and processing and complementation by cell fusion; molecular analysis by cloning human OAT to examine the mutations and their effect on the processing of OAT RNA and its translate; delineation of the ornithine and guanidino metabolism of ocular tissues and culture SV40 transformed human retinal pigment epithelium; long term ophthalmologic and biochemical assessment of patients on diet therapy and OAT analysis in the livers of mutagenized mice. These studies should provide insight not only into the mechanism of chorioretinal degeneration and cataract formation in GA but also suggest possible explanations for related disorders. Increased knowledge of the heterogeneity and response to experimental therapy should lead to the development of effective therapy.